Multistep flow synthesis of 5-amino-2-aryl-2h-[1,2,3]-triazole-4-carbonitriles

Article abstract of DOI:10.1002/chem.201402074

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.

Full text of DOI:10.1002/chem.201402074

DOI: 10.1002/chem.201402074
Full Paper
&
Flow Chemistry
Multistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4-
carbonitriles
Jꢀrꢁme Jacq and Patrick Pasau*[a]
Abstract: 1,2,3-Triazole has become one of the most impor-
tant heterocycles in contemporary medicinal chemistry. The
development of the copper-catalyzed Huisgen cycloaddition
has allowed the efficient synthesis of 1-substituted 1,2,3-tria-
zoles. However, only a few methods are available for the se-
lective preparation of 2-substituted 1,2,3-triazole isomers. In
this context, we decided to develop an efficient flow synthe-
sis for the preparation of various 2-aryl-1,2,3-triazoles. Our
strategy involves a three-step synthesis under continuous-
flow conditions that starts from the diazotization of anilines
and subsequent reaction with malononitrile, followed by nu-
cleophilic addition of amines, and finally employs a catalytic
copper(II) cyclization. Potential safety hazards associated
with the formation of reactive diazonium species have been
addressed by inline quenching. The use of flow equipment
allows reliable scale up processes with precise control of the
reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles
has been achieved in good yields with excellent selectivities,
thus providing a wide range of 1,2,3-triazoles.
Introduction
Since the discovery of the copper-catalyzed azide–alkyne cyclo-
addition (CuAAC), N-substituted 1,2,3-triazoles have become
one of the most exploited heterocycles in life and materials sci-
ences.[1] Many general synthetic methodologies have been de-
veloped for regioselective access to 1,4- and 1,5-substituted
1,2,3-triazoles.[2] In contrast, the regioselective formation of 2-
substituted 1,2,3-triazoles remains challenging for triazole deri-
vatization. 2-Aryl-1,2,3-triazoles are especially interesting deriv-
atives because they are widely used as biologically active com-
pounds.[2b,3] The main synthetic approaches involve condensa-
tion with arylhydrazines[4a,b] or N-2-arylation processes. Howev-
er, arylation strategies usually face competitive N-1-substitution
reactions, thus hampering their utility.[3b,4c] Recently, high levels
of 2-selectivities have been achieved under basic conditions
that start from 4,5-dibromo-1,2,3-triazole or by using copper-
and palladium-based catalytic systems.[5] Nevertheless, the
scope of such methodologies is limited regarding the 4- and 5-
substitutions of 1,2,3-triazoles.
Scheme 1. The described current strategy for the synthesis of 5-amino-2-
aryl-2H-[1,2,3]-triazole-4-carbonitrile.
aniline and subsequent reaction with malononitrile, followed
by nucleophilic addition of an amine, and finally employs
a copper(II)-mediated cyclization (Scheme 1).[6,7] A significant
drawback of this methodology is the generation and isolation
of highly reactive and sensitive aryl diazonium species. This
issue raises significant safety concerns especially for large-scale
reactions.[8]
In terms of the biological activities of 2-substitued 1,2,3-tria-
zoles,
5-amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles
are
known as antifungal agents.[6] Thus, an improved synthetic
pathway would allow further evaluation of their biological
properties. The current strategy to access these compounds in-
volves a four-step synthesis that starts from diazotization of
Increasing process safety has been outlined as a major asset
of flow chemistry. In this regard, the development of flow
chemistry as an enabling technology has been supported by
both academia and industry. In addition, flow reactors offer
several advantages over batch synthesis, including improved
heat and mass transfer and ease of scale-up. Due to small-
volume reactors in a contained environment, flow chemistry
can safely generate reactive intermediates in a continuous-flow
stream. For example, continuous-flow processes have enabled
the efficient synthesis of aryl diazonium species with precise
[a] Dr. J. Jacq, Dr. P. Pasau
UCB Biopharma
Avenue de l’Industrie
1420 Braine l’Alleud (Belgium)
E-mail: patrick.pasau@ucb.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402074.
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control of the reaction conditions.[9] These intermediates have
been used for the continuous synthesis of azide building
blocks[9a,b] and for the Sandmeyer reaction,[9c] Heck coupling,[9d]
and a multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazo-
les.[9h] To the best of our knowledge, in all the examples de-
scribed in a flow mode, the aryl diazonium species have been
involved as radical precursors. Herein, we describe the forma-
tion of diazonium intermediates and the subsequent nucleo-
philic attack of malononitrile to obtain 2-arylhydrazonomalono-
nitriles in one flow stream. Efficiency and safety features of the
process allowed us to rapidly scale up this sequence. Fully au-
tomated flow equipment enabled the production of a focused
library of 2-arylhydrazonoacetamidines by the addition of vari-
ous amine compounds to 2-arylhydrazonomalononitriles. Final-
ly, 5-amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles were ob-
tained in good yields with excellent regioselectivities by using
a new catalytic copper(II) oxidative cyclization.
HCl (used to obtain the more stable diazonium salt). It is also
apparent that no base was needed to perform the reaction.
We postulate that a diazonium intermediate is consumed rap-
idly upon the addition of the malononitrile nucleophile, which
results from the presence of the tert-butanolate moiety.[12] By
using these conditions, we could obtain high yields (90–99%)
of the desired hydrazones 1a–f from the corresponding ani-
lines. It is noteworthy that similar yields were obtained with
electron-donating or electron-withdrawing groups (Table 1),
Table 1. Synthesis of 2-arylhydrazonomalononitriles 1a–f.
Entry
Ar
Isolated
product
Scale
[mmol]
Yield
[%][a]
1
2
3
4
5
6
Ph
1a
1b
1c
1d
1e
1 f
40
40
40
16
16
16
98
92
98
99
90
95
4-MeOC6H4
4-MeC6H4
4-FC6H4
4-NO2C6H4
4-EtO2CC6H4
[a] Yield of the isolated product after solvent evaporation.
Results and Discussion
Synthesis of 2-arylhydrazonomalononitriles
Our strategy to synthesize 5-amino-2-aryl-2H-[1,2,3]-triazole-4-
carbonitriles started with commercially available anilines and
used tert-butyl nitrite (tBuONO) as an oxidant. tBuONO is
known as a nonexplosive stable substitute for sodium nitrite,
thus allowing the formation of diazonium intermediates in
batch and flow processes.[9,10] Diazonium species may decom-
pose rapidly and uncontrollably, thus resulting in explosions
and making their use hazardous in conventional batch reactors
especially on a large scale.[8,11] For the synthesis of 2-arylhydra-
zonomalononitriles, malononitrile was solubilized with aniline
to trap the diazonium species as it is formed in the flow
stream, thus avoiding the accumulation and handling of explo-
sive intermediates. In a typical experiment (Scheme 2), a solu-
tion of aniline (0.4m) and malononitrile (0.4m) in acetonitrile
was combined with a solution of tert-butyl nitrite (0.52m) in
acetonitrile through a T-mixing piece and was directed to a per-
fluoroalkoxy (PFA) polymer tubular flow reactor maintained at
room temperature to obtain 2-arylhydrazonomalononitriles in
10 minutes and in a yield of greater than 90% of the isolated
product.
thus highlighting that there was no electronic effect from the
C4 substituents. Finally, the optimized procedures allowed us
to rapidly process various 2-arylhydrazonomalononitriles on
a scale of up to 40 millimoles by using the same equipment as
for the small-scale experiments (Figure 1). This outcome repre-
sents a productivity for such a process of 16.8 mmolhÀ1
.
Synthesis of 2-arylhydrazono-2-cyanoacetamidines
We next turned our attention to the synthesis of amidines
based on the direct addition of amines to nitriles. This reaction
Interestingly, the diazonium species is generated in an or-
ganic solvent without the addition of a strong acid, such as
Figure 1. Uniqsis FlowSyn and setup used for the synthesis of 2-arylhydrazo-
Scheme 2. Flow synthesis of 2-arylhydrazonomalononitrile.
nomalononitrile.
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is mainly driven by both the electrophilicity of the cyano
group and the nucleophilicity of the amine functionality. It
often requires the use of a Lewis acid or aluminum amides,
high excess of the reagents, and high temperature.[13]
trile (1:1, 0.4m) was combined with a second flow stream of
tert-butyl nitrite in acetonitrile (0.52m) through a T-mixing
piece (total flow rate=0.30 mLminÀ1). The mixed solution was
passed through a PFA flow reactor at room temperature
(5.0 mL). The stream containing hydrazine 1a was telescoped
with ammonia in methanol (7m, flow rate=0.30 mLminÀ1),
and the mixture was fed through two PFA flow reactors
(10.0 mL) at 1108C.
In our initial investigations, we examined the addition of am-
monia to 2-phenylhydrazonomalononitrile (1a) to synthesize
3,3-diamino-2-(4-phenylazo)-acrylonitrile (2a; Scheme 3). As
We were pleased to observe that this system facilitated
quantitative conversion into the desired product 2a with
a high-purity profile. Finally, the system was run in a scale-up
process as described for 6.25 hours at steady state. By the end
of the process, 4.1 grams of product were obtained with good
purity by simple evaporation of the solvents and excess of am-
monia (Figure 2).
Scheme 3. Flow synthesis of 2a.
a gas, ammonia requires safety assessment, especially for
larger-scale reactions. Although the use of gaseous ammonia
has been described in continuous-flow systems,[14] we pre-
ferred to start from solutions of ammonia in methanol.[15] Fur-
thermore ammonia in solutions at high temperature necessi-
tates pressurization of the system. In the batch mode, sealed
vessels are required for containment. Interestingly, in a continu-
ous-flow process, simple back-pressure regulators allow imme-
diate pressurization of the system, thus maintaining controlled
solubilization of the gaseous reagent and a safer environment.
The reaction was performed by using an excess of ammonia in
methanol (7m) and a back-pressure regulator of 8 bar to con-
tain the reaction mixture as an homogeneous liquid phase. In
practice, a stream containing hydrazone 1a was mixed with
a solution of ammonia in methanol (loaded through loops of
2.0 mL) in a T-mixing piece. The combined flow stream at
0.4 mLminÀ1 entered a coil reactor (10.0 mL) heated at 1108C.
High conversion (95%) into 2-arylhydrazono-2-cyanoacetami-
dine 2 with high purity was achieved in a residence time of
25 minutes.
Figure 2. Reactor design for the multistep flow synthesis of 2a.
As part of our ongoing efforts to develop automated flow
processes for focused library production, we describe the use
of an automated system to generate a collection of 2-arylhy-
drazono-2-cyanoacetamidines 2, which are key intermediates
for triazole synthesis. Various cyclic amines 3, such as pyrroli-
dine 3a, piperidine 3b, morpholine 3c, and piperazine 3d,
were combined with the different hydrazone derivatives 1a–f
obtained in the first step. Equimolar solutions of amines 3a–d
in ethanol and hydrazones 1a–f in THF/ethanol mixtures were
prepared and allocated positions in a Gilson liquid handler. De-
pending of the nature of the hydrazone, various amounts of
THF were used to obtain complete dissolution of the starting
material at 0.25m. The liquid handler was used to inject feed
solutions into the flow stream and to collect 2-arylhydrazonoa-
cetamidines 2a–p.
The ability to perform multistep sequences in a continuous-
flow stream by telescoping various reagents enhances the
access to highly functionalized
In a typical sequence, sample loops A and B (5 mL) were
loaded with solutions of the starting materials from the auto-
compounds. Such developments
represent a significant challenge
considering dispersion phenom-
ena, solvent compatibility, and
byproduct formation.[16] To this
end, an automated system was
set up to combine the synthesis
of 2-arylhydrazonomalononitrile
and the addition of ammonia in
a
continuous
(Scheme 4). A flow stream of ani-
line and malononitrile in acetoni- Scheme 4. Multistep flow synthesis of 2a.
process
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sampler, switched into line, and driven with a constant stream
of ethanol. After passing through a T-mixing piece, the com-
bined flow streams were directed through a PFA-coated stain-
less-steel reactor (16 mL) heated at 1008C. The resulting reac-
tion mixture passed through a back-pressure regulator and
a UV-detector to trigger collection at the liquid handler
(Figure 3 and Scheme 5). In this way, 15 sequential reactions
Table 2. Synthesis of 2a and automated library synthesis of 2-arylhydra-
zono-2-cyanoacetamidines 2b–p.
Entry
1
Amine
Isolated product
Yield
[%][a]
1
2
1a
1a
NH3
2a
2b
95[b]
96
3a
3
4
5
1a
1a
1a
3b
3c
3d
2c
2d
2e
96
91
98
6
7
1b
1b
3a
3b
2 f
72
90
Figure 3. Automated Vapourtec system with Gilson liquid handler (the setup
for the library synthesis).
2g
8
9
1b
1b
1c
1c
3c
3d
3b
3c
2h
2i
86
88
90
95
10
11
2j
Scheme 5. Automated library flow synthesis of 2-arylhydrazono-2-cyanoace-
tamidines 2b–p.
2k
were performed by the automated system without any manual
input. All the products were isolated in good-to-excellent
yields by parallel evaporation (Table 2). No clogging or cross-
contamination were observed in any case.
12
13
14
1c
1d
1d
3d
3a
3b
2l
98
89
87
2m
2n
Synthesis of 5-amino-2-aryl-2H-[1,2,3]-triazole-4-carbo-
nitriles
The oxidative cylization of 2-arylhydrazonoacetamidines 2 has
been previously described with two equivalents of copper ace-
tate in pyridine at 608C to form triazoles in good yields.[7] Our
primary objective was to develop an efficient flow process
based on the batch procedure. The reactions were performed
in DMF to solubilize the starting materials, and a flow system
was assembled (Scheme 6). A solution of copper acetate in
15
1e
3c
2o
87
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Table 2. (Continued)
Entry
1
Amine
Isolated product
Yield
[%][a]
16
1 f
3c
2p
95
[a] All reactions were performed on a scale of 1.25 mmol. [b] The reaction
was performed on scale of 0.46 mmol according to the setup described
in Scheme 3; product 2a was obtained with 90% purity (determined by
LC-MS analysis).
Scheme 7. Setup for the synthesis of 5-amino-2-aryl-2H-[1,2,3]-triazole-4-car-
bonitriles 4a–p.
35 minutes was suitable for full consumption of the starting
material. Collected solutions of the fractions were evaporated
and the desired triazole products 4 could be isolated by solu-
bilizing the crude material in dichloromethane to precipitate
inorganic salts and filtration on a cartridge filled with a pad of
celite and silica gel. 5-Amino-2-aryl-2H-[1,2,3]-triazole-4-carbon-
itriles 4a–p were thus generated in flow from 2-arylhydrazo-
noacetamidines 3a–p in moderate-to-excellent yields (Table 3).
Scheme 6. Flow synthesis of 1,2,3-triazoles adapted from the batch proce-
dure.
Table 3. Synthesis of 5-amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles 4a–
p.
DMF (0.25m) was mixed with a solution of 3,3-diamino-2-phe-
nylazo-acrylonitrile (2a; 0.25m, 1.0 equiv) and pyridine
(8 equiv) in DMF. The resulting flow stream (total flow rate=
0.24 mLminÀ1) was delivered to a PFA coil reactor (5 mL)
heated at 1208C. We observed complete conversion of the
starting material; however, isolation of product 4a proved tedi-
ous due to the large amount of copper residues, which
prompted us to evaluate the catalytic protocols.
Entry
Acetamide
Isolated product
Yield
[%][a]
1
2
3
2a
2b
2c
4a
4b
4c
50
87
95
Rapid optimization of the reactions parameters in the batch
mode revealed that a catalytic amount of Cu(OAc)2 (20 mol%)
led to a good conversion of starting material 2a (75%) in DMF
at 808C in an air atmosphere. Accordingly, we explored the
scope of this result with various oxidants, such as NaOCl, H2O2,
O2, tert-butyl hydroperoxide, and NaIO4 (2.0 equiv). Sodium pe-
riodate (NaIO4) clearly appeared to be the most effective re-
agent by giving a clean conversion into the desired 1,2,3-tria-
zole product in the presence or absence of pyridine.[17] With
optimal conditions in hand, we performed this critical oxidative
cyclization step as a flow process (Scheme 7). Solutions of 2-ar-
ylhydrazonoacetamidine 3 in DMF (0.2m) and solutions of DMF
containing NaIO4 (1.2 equiv, 0.24 mm) and Cu(OAc)2 (10 mol%,
0.02m) were separately loaded into individual loops (1.0 mL)
mounted on the Uniqsis FlowSyn equipment. The solutions
were combined at in a T-mixing piece connector, and the re-
sulting flow was passed through a PFA flow coil (14 mL)
heated at 1208C. A back-pressure regulator (7 bar) was placed
in a sonication bath (Scheme 7) to avoid clogging because of
the precipitation of inorganic species.[18] A residence time of
4
5
2d
2e
4d
4e
68
48
6
7
2 f
4 f
82
98
2g
4g
8
2h
4h
92
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batch-mode approach in terms of praticability, safety, and
yield.
Table 3. (Continued)
Entry
Acetamide
Isolated product
Yield
[%][a]
Experimental Section
9
2i
4i
22
80
93
General
Reagents were obtained from commercial sources and were used
without purification. The removal of the solvent under reduced
pressure was carried out on a standard rotary evaporator and com-
pleted by using a vacuum pump. H and 13C NMR spectra were re-
corded on a Bruker Avance 400 spectrometer with the residual sol-
vent peak as an internal reference ([D6]DMSO=2.50 and
39.52 ppm for 1H and 13C NMR, respectively). 1HNMR resonances
are reported to the nearest 0.01 ppm. 13CNMR resonances were re-
10
11
12
2j
2k
2l
4j
4k
4l
1
1
ported to the nearest 0.1 ppm. The multiplicity of HNMR signals
are indicated as s=singlet, d=doublet, t=triplet, m=multiplet,
br=broad, or combinations of thereof. Coupling constants J are
quoted in Hz and are reported to the nearest 0.1 Hz. Where appro-
priate, averages of the signals that display multiplicity were used
to calculate the value of the coupling constant. IR spectra were
measured of neat samples on a PerkinElmer Spectrum 2000 FTIR
spectrometer by using universal attenuated total reflection (ATR)
sampling accessories. LC-MS analysis was performed on a QM
Waters triple quadrupole mass spectrometer. This spectrometer
was equipped with an ESI source and an HPLC Waters 2795 quater-
nary pump with a diode-array detector (l=210–400 nm). Data
were acquired in a full MS scan from m/z 50–750 in the positive
and negative modes with basic elution. Gradient elution was car-
ried out with water, acetonitrile, and ammonium formate in water
(630 mgLÀ1)+NH4OH (30%, 500 mLLÀ1). The m/z value is reported
to the nearest mass unit. High-resolution mass-spectrometric analy-
sis was performed with a Waters Micromass LCT Premier spectrom-
eter by means of time-of-flight with positive ESI. This spectrometer
was equipped with an ESI source and an UPLC Waters with diode-
array detector (l=210–400 nm). Data were acquired in a full MS
scan from m/z 50 to 1000 in the positive mode with an acid elu-
65
97
13
2m
4m
14
15
16
2n
2o
2p
4n
4o
4p
77
83
61
tion. Gradient elution was carried out with formic acid (0.5 mLLÀ1
)
[a] All reactions performed on a 0.2 mmol scale.
in acetonitrile/water (5:95) and formic acid (0.375 mLLÀ1) in aceto-
nitrile. All the flow reactions were performed by using etheir a Va-
pourtec R-series flow platform or a Uniqsis FlowSyn flow system.
Conclusion
General procedure A for the synthesis 2-arylhydrazonomalo-
nonitriles 1a–f
We have demonstrated that flow chemistry is a promising and
powerful enabling method to facilitate and accelerate the
preparation of biological relevant heterocyclic compounds. We
designed a sequence of reactions to safely scale up the pro-
duction of hazardous diazonium intermediates and the use of
a solution of ammonia in one flow stream. An automated flow
device enabled us to quickly prepare a collection of key com-
pounds in adequate quantities for further derivatization. A
novel catalytic copper oxidative cyclization in a flow mode pro-
vided a more sustainable-chemistry practice for the synthesis
of 5-amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles 4a–p. The
final compounds were obtained with excellent purities and in
good yields without the need for complex downstream pro-
cess. Overall, the synthetic pathway allowed the synthesis of 2-
aryl-1,2,3-triazoles with complete selectivity without traces of
other isomers being observed. Furthermore, such a sequence
represents several improvements relative to the conventional
A solution of aniline (0.4m in MeCN) and malononitrile (1 equiv,
0.4m) and a solution of tert-butyl nitrite (0.52m) in MeCN were
pumped at a flow rate of 0.7 mLminÀ1 each. The starting materials
mixed in a arrowhead T-mixing piece (I.D.=1.4 mm) and the reac-
tion solution (combined flow rate=1.4 mLminÀ1) passed through
a coil reactor (14 mL; I.D.=1 mm) at room temperature and exited
the flow system through a back-pressure regulator (7 bar). Crude
products 1 were obtained by evaporation of the solvent.
Phenylhydrazonomalononitrile (1a): Product 1a was obtained
from aniline according to general procedure A. The reaction was
performed on a scale of 40 mmol. The product was obtained as
1
a yellow–green solid (6.66 g, 39.2 mmol, 98%). H NMR (400 MHz,
[D6]DMSO): d=7.44 (m, 4H), 7.22 ppm (t, 1H, J=6.8 Hz); 13C NMR
(101 MHz, [D6]DMSO): d=141.4 (C), 129.5 (2ꢃCH), 125.8 (CH), 116.5
(2ꢃCH), 114.4 (C), 110.0 (C), 84.5 ppm (C); FTIR (neat): n˜ =3192,
3131, 3060, 2232, 2213, 1542, 1468, 1442, 1279, 754, 692 cmÀ1; LC-
MS: m/z 168.9 [MÀH]À.
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(4-Methoxyphenyl)hydrazonomalononitrile (1b): Product 1b was
obtained from 4-methoxyaniline according to general procedure A.
The reaction was performed on scale of 40 mmol. The product was
obtained as a brown solid (7.36 g, 36.8 mmol, 92%). 1H NMR
(400 MHz, [D6]DMSO): d=7.42 (d, 2H, J=9.1 Hz), 6.99 (d, 2H, J=
9.1 Hz), 3.75–3.79 ppm (m, 3H); 13C NMR (101 MHz, [D6]DMSO): d=
157.9 (C), 135.3 (C), 118.4 (2ꢃCH), 115.1 (2ꢃCH), 110.6 (C), 83.2 (C),
55.8 ppm (CH3); FTIR (neat): n˜ =3195, 3132, 3061, 2360, 2218, 1612,
1545, 1509, 1439, 1242, 1164, 1027, 825, 724 cmÀ1; LC-MS: m/
z 199.1 [MÀH]À.
(4-Methylphenyl)hydrazonomalonotrile (1c): Product 1c was ob-
tained from 4-methylaniline according to general procedure A. The
reaction was performed on scale of 40 mmol. The product was ob-
tained as a yellow–green solid (7.21 g, 39.2 mmol, 98%). 1H NMR
(400 MHz, [D6]DMSO): d=7.37 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=
8.4 Hz), 3.33–3.49 (brs, 1H), 2.30 ppm (s, 3H); 13C NMR (101 MHz,
[D6]DMSO): d=139.5 (C), 135.8 (C), 130.3 (2ꢃCH), 116.8 (2ꢃCH),
114.8 (C), 110.4 (C), 84.1 (C), 20.9 ppm (CH3); FTIR (neat): n˜ =3233,
3204, 2226, 2215, 1608, 1545, 1437, 1281, 810, 711 cmÀ1; LC-MS: m/
z 183.0 [MÀH]À.
(4-Fluorophenyl)hydrazonomalononitrile (1d): Product 1d was
obtained from 4-fluoroaniline according to general procedure A.
The reaction was performed on scale of 16 mmol. The product was
obtained as a brown solid (2.98 g, 15.84 mmol, 99%). 1H NMR
(400 MHz, [D6]DMSO): d=7.49 (m, 2H), 7.27 ppm (t, 2H, J=8.7 Hz);
13C NMR (101 MHz, [D6]DMSO): d=159.9 (C, J=242.8 Hz), 138.4 (C),
118.4 (2ꢃCH, J=8.8 Hz), 116.3 (2ꢃCH, J=23.5 Hz), 114.6 (C), 110.2
(C), 84.1 ppm (C); FTIR (neat): n˜ =3218, 3159, 3078, 2218, 1623,
1558, 1509, 1296, 1220, 832, 730 cmÀ1; LC-MS: m/z 187.1 [MÀH]À.
monia in methanol was pressurized at 0.6 bar. The resulting stream
was pumped (at 0.60 mLminÀ1) through two consecutive coil reac-
tors (10.0 mL, I.D.=1 mm) heated at 1108C (total residence time=
33 min). The output stream passed through a back-pressure regu-
lator (8 bar). After steady state (i.e., 1h), the stream was collected
in a flask for 6.25 h. The collected fraction was evaporated and
product 2a was obtained as a black solid (4.1 g, 21.9 mmol, 97%).
1H NMR (400 MHz, [D6]DMSO): d=7.55 (d, 2H, J=8.0 Hz), 7.32 (t,
2H, J=7.5 Hz), 7.24 (s, 3H), 7.12 ppm (t, 1H, J=7.2 Hz); 13C NMR
(101 MHz, [D6]DMSO): d=161.3 (C), 153.0 (C), 128.6 (2ꢃCH), 125.5
(CH), 120.3 (2ꢃCH), 115.5 (C), 91.2 ppm (C); FTIR (neat): n˜ =3407,
3347, 3199, 2184, 1618, 1535, 1388, 755, 697, 648 cmÀ1; LC-MS: m/
z 186.1 [MÀH]À; HRMS (ESI): m/z calcd for C9H9N5: 188.0936; found:
188.0932.
General procedure B for the synthesis of 2-arylhydrazono-2-
cyanoacetamidines (2b–p)
Sample loop A (5.0 mL) was filled with a stock solution of arylhy-
drazonomalononitrile 1a–f (1.25 mmol, 0.25 mm) in EtOH/THF mix-
tures and sample loop B (5.0 mL) was filled with a stock solution of
amine 3a–d (pyrrolidine, piperidine, morpholine, or piperazine;
1.25 mmol, 0.25 mm) in EtOH. The two sample loops were simulta-
neously switched into line and the starting material solutions were
pumped through the system at a flow rate of 0.25 mLminÀ1 each,
driven by pumps with a constant stream of EtOH. The starting ma-
terials were mixed in a T-mixing piece (I.D.=0.5 mm), and the reac-
tion solution (combined flow rate=0.50 mLminÀ1) passed through
a PFA-coated stainless-steel reactor (16.0 mL, I.D.=2.1 mm) heated
at 1008C (residence time=33 min) and exited the flow system
through a back-pressure regulator (7 bar). The output stream was
collected on the Gilson platform in a tube and products 2b–p
were obtained by evaporation of the solvent.
(4-Nitrophenyl)hydrazonomalononitrile (1e): Product 1e was ob-
tained from 4-nitroaniline according to general procedure A. The
reaction was performed on scale of 16 mmol. The product was ob-
tained as a dark-red solid (3.01 g, 14.4 mmol, 90%). 1H NMR
(400 MHz, [D6]DMSO): d=7.55 (d, 2H, J=7.5 Hz), 7.33 (t, 2H,
7.6 Hz), 7.20 (brs, 1H), 7.12 ppm (t, 1H, J=7.3 Hz); 13C NMR
(101 MHz, [D6]DMSO): d=147.2 (C), 144.3 (C), 125.9 (2ꢃCH), 117.1
(2ꢃCH), 114.2 (C), 109.9 (C), 88.9 ppm (C); FTIR (neat): n˜ =3223,
2-Phenylhydrazono-2-cyano-N,N-butylmethylen-acetamidine
(2b): Product 2b was obtained from product 1a and pyrrolidine
3a according to general procedure B. Compound 1a was dissolved
in an EtOH/THF mixture (95:5, v/v). Product 2b was obtained as an
orange solid (290 mg, 1.20 mmol, 96%). 1H NMR (400 MHz,
[D6]DMSO): d=7.48 (d, 2H, J=7.6 Hz), 7.32 (t, 2H, J=7.5 Hz), 7.22–
7.28 (m, 2H), 7.10 (t, 1H, J=7.2 Hz), 3.58–3.70 (m, 4H), 1.94 ppm (t,
4H, J=6.3 Hz); 13C NMR (101 MHz, [D6]DMSO): d=158.3 (C), 153.6
(C), 128.7 (2ꢃCH), 125.2 (CH), 120.4 (2ꢃCH), 117.1 (C), 92.4 (C), 49.7
(2ꢃCH2), 24.8 ppm (2ꢃCH2); FTIR (neat): n˜ =3383, 3302, 3212,
2980, 2181, 1560, 1478, 1376, 1357, 1305, 1220, 761, 697 cmÀ1; LC-
MS: m/z 242.18 [M+H]+; HRMS (ESI): m/z calcd for C13H15N5:
242.1405; found: 242.1411.
3092, 2225, 1560, 1508, 1459, 1339, 1279, 1109, 849, 751, 691 cmÀ1
LC-MS: m/z 214.1 [MÀH]À.
;
(4-Carbethoxyphenyl)hydrazonomalononitrile (1 f): Product 1 f
was obtained from ethyl 4-aminobenzoate according to general
procedure A. The reaction was performed on scale of 16 mmol.
The product was obtained as a yellow solid (3.68 g, 15.1 mmol,
95%). 1H NMR (400 MHz, [D6]DMSO): d=7.99 (d, 2H, J=8.8 Hz),
7.56 (d, 2H, J=8.8 Hz), 4.30 (q, 2H, J=7.1 Hz), 3.21–3.57 (brs, 1H),
1.32 ppm (t, 3H, J=7.1 Hz); 13C NMR (101 MHz, [D6]DMSO): d=
165.1 (C), 145.5 (C), 130.8 (2ꢃCH), 126.3 (C), 116.3 (2ꢃCH), 114.3
(C), 109.8 (C), 86.5 (C), 60.7 (CH2), 14.2 ppm (CH3); FTIR (neat): n˜ =
3227, 3197, 3059, 2230, 1701, 1606, 1544, 1471, 1265, 1107, 854,
770, 701 cmÀ1; LC-MS: m/z 241.1 [MÀH]À.
2-Phenylhydrazono-2-cyano-N,N-pentamethylen-acetamidine
(2c): Product 2c was obtained from product 1a and piperidine 3b
according to general procedure B. Compound 1a was dissolved in
an EtOH/THF mixture (95:5, v/v). Product 2c was obtained as
a
brown solid (306 mg, 1.20 mmol, 96%). 1H NMR (400 MHz,
[D6]DMSO): d=7.54–7.61 (brs,1H), 7.49 (d, 2H, J=7.5 Hz), 7.32 (t,
2H, J=7.5 Hz), 7.11 (t, 1H, J=7.2 Hz), 3.51–3.63 (m, 4H), 1.59–
1.70 ppm (m, 6H); 13C NMR (101 MHz, [D6]DMSO): d=162.1 (C),
153.6 (C), 128.6 (2ꢃCH), 125.3 (CH), 120.4 (2ꢃCH), 117.0 (C), 92.7
(C), 49.3 (2ꢃCH2), 25.6 (2ꢃCH2), 23.6 ppm (CH2); FTIR (neat): n˜ =
3297, 3203, 2933, 2184, 1619, 1560, 1478, 1379, 1313, 1204, 992,
764, 694 cmÀ1; LC-MS: m/z 256.24 [M+H]+; HRMS (ESI): m/z calcd
for C14H17N5: 256.1562; found: 256.1554.
Multistep synthesis of 3,3-diamino-2-phenylazo-acrylonitrile
(2a)
A stock solution of aniline (0.40m) and malononitrile (0.40m) in
acetonitrile and a stock solution of tert-butyl nitrite (0.52m) in ace-
tonitrile were pumped at a flow rate of 0.15 mLminÀ1 (for each so-
lution) and were combined in a T-mixing piece (I.D.=0.5 mm). The
mixed flow stream was pumped through a PFA reactor (5.0 mL,
I.D.=1 mm) at room temperature and a flow rate of 0.30 mLminÀ1
The output stream was combined in a T-mixing piece (I.D.=
0.5 mm) with a constant stream of ammonia in methanol (7m)
pumped at a flow rate of 0.30 mLminÀ1. The stock solution of am-
.
2-Phenylhydrazono-2-cyano-N,N-(3-oxopentamethylen)-acetami-
dine (2d): Product 2d was obtained from product 1a and mor-
pholine 3c according to general procedure B. Compound 1a was
dissolved in an EtOH/THF mixture (95:5, v/v). The product 2d was
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obtained as an orange solid (292 mg, 1.14 mmol, 91%). 1H NMR
(400 MHz, [D6]DMSO): d=7.72 (brs, 1H), 7.51 (d, 2H, J=7.5 Hz),
7.34 (t, 2H, J=7.5 Hz), 7.14 (t, 1H, J=7.2 Hz), 3.71 (m, 4H),
3.62 ppm (m, 4H); 13C NMR (101 MHz, [D6]DMSO): d=162.5 (C),
153.4 (C), 128.7 (2ꢃCH2), 125.7 (CH), 120.5 (2ꢃCH2), 116.9 (C), 92.7
(C), 66.0 (2ꢃCH2), 48.7 ppm (2ꢃCH2); FTIR (neat): n˜ =3428, 3275,
3079, 2973, 2892, 2852, 2194, 1626, 1552, 1490, 1356, 1314, 1219,
1119, 1007, 762, 686 cmÀ1; LC-MS: m/z 258.20 [M+H]+; HRMS (ESI):
m/z calcd for C13H15N5O: 258.1355; found: 258.1346.
was dissolved in an EtOH/THF mixture (67:33, v/v). Product 2i was
obtained as a brown solid (315 mg, 1.10 mmol, 88%; mixture of
1
isomers 1 and 2). H NMR (400 MHz, [D6]DMSO): isomer 1: d=7.47
(d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=8.6 Hz), 3.76 (s, 3H), 3.60 (m, 4H),
2.88 ppm (m, 4H); isomer 2: d=7.47 (d, 2H, J=8.7 Hz), 6.90 (d,
2H, J=8.6 Hz), 3.76 (s, 3H), 3.51 (m, 4H), 2.81 ppm (m, 4H);
13C NMR (101 MHz, [D6]DMSO): d=157.6 (C), 147.6 (C), 132.7 (C),
121.6 (2ꢃCH), 113.9 (2ꢃCH), 99.7 (C), 92.0 (C), 55.2 (2ꢃCH3), 49.5
(2ꢃCH2), 45.5 ppm (2ꢃCH2); FTIR (neat): n˜ =2911, 2179, 1541,
1490, 1375, 1313, 1240, 1000, 832 cmÀ1; LC-MS: m/z 287.18 [M+
H]+; HRMS (ESI): m/z calcd for C14H18N6O: 287.162; found:
287.1614.
2-Phenylhydrazono-2-cyano-N,N-(3-nitrosopentamethylen)-acet-
amidine (2e): Product 2e was obtained from 1a and piperazine
3d according to general procedure B. Compound 1a was dissolved
in an EtOH/THF mixture (95:5, v/v). Product 2e was obtained as
2-(4-Methylphenylhydrazono)-2-cyano-N,N-pentamethylen-acet-
amidine (2j): Product 2j was obtained from 1c and piperidine 3b
according to general procedure B. Compound 1c was dissolved in
an EtOH/THF mixture (56:44, v/v). Product 2j was obtained as
a
red solid (314 mg, 1.23 mmol, 98%). 1H NMR (400 MHz,
[D6]DMSO): d=7.49 (d, 2H, J=7.6 Hz), 7.32 (t, 2H, J=7.6 Hz), 7.11
(t, 1H, J=7.2 Hz), 3.52 (m, 4H), 2.79 ppm (m, 4H); 13C NMR
(101 MHz, [D6]DMSO): d=162.4 (C), 153.6 (C), 128.6 (2ꢃCH), 125.4
(CH), 120.4 (2ꢃCH), 117.0 (C), 92.8 (C), 49.8 (2ꢃCH2), 45.6 ppm (2ꢃ
CH2); FTIR (neat): n˜ =3309, 2180, 1542, 1475, 1364, 1305, 1210,
1097, 993, 763, 692 cmÀ1; LC-MS: m/z 257.10 [M+H]+; HRMS (ESI):
m/z calcd for C13H16N6: 257.1515; found: 257.1505.
a
brown solid (302 mg, 1.12 mmol, 90%). 1H NMR (400 MHz,
[D6]DMSO): d=7.46–7.53 (brs, 1H), 7.40 (d, 2H, J=8.1 Hz), 7.13 (d,
2H, J=8.1 Hz), 3.49–3.59 (m, 4H), 2.29 (s, 3H), 1.53–1.71 ppm (m,
6H); 13C NMR (101 MHz, [D6]DMSO): d=162.2 (C), 151.5 (C), 134.6
(C), 129.2 (2ꢃCH), 120.3 (2ꢃCH), 117.2 (C), 92.3 (C), 49.3 (2ꢃCH2),
25.6 (2ꢃCH2), 23.7, 20.7 ppm (CH3); FTIR (neat): n˜ =3358, 2927,
2852, 2187, 1627, 1535, 1482, 1365, 1310, 1207, 1084, 992,
816 cmÀ1; LC-MS: m/z 270.23 [M+H]+; HRMS (ESI): m/z calcd for
C15H19N5: 270.1718; found: 270.1715.
2-(4-Methoxyphenylhydrazono)-2-cyano-N,N-butylmethylen-
acetamidine (2 f): Product 2 f was obtained from 1b and pyrroli-
dine 3a according to general procedure B. Compound 1b was dis-
solved in an EtOH/THF mixture (67:33, v/v). Product 2 f was ob-
tained as a dark-green solid (244 mg, 0.90 mmol, 72%). 1H NMR
(400 MHz, [D6]DMSO): d=7.47 (d, 2H, J=8.7 Hz), 7.13 (brs, 1H),
6.89 (d, 2H, J=8.8 Hz), 3.76 (s, 3H), 3.63 (m, 4H), 1.94 ppm (m,
4H); 13C NMR (101 MHz, [D6]DMSO): d=158.3 (C), 157.4 (C), 121.5
(2ꢃCH), 117.5 (C), 113.9 (2ꢃCH), 105.5 (C), 91.5 (C), 55.2 (CH3), 49.5
(2ꢃCH2), 24.9 ppm (2ꢃCH2); FTIR (neat): n˜ =3457, 3321, 2972,
2182, 1603, 1557, 1478, 1379, 1357, 1225, 1173, 1104, 1027,
828 cmÀ1; LC-MS: m/z 272.20 [M+H]+; HRMS (ESI): m/z calcd for
C14H17N5O: 272.1511; found: 272.1512.
2-(4-Methylphenylhydrazono)-2-cyano-N,N-(3-oxopentamethy-
len)-acetamidine (2k): Product 2k was obtained from 1c and mor-
pholine 3c according to general procedure B. Compound 1c was
dissolved in an EtOH/THF mixture (56:44, v/v). Product 2k was ob-
tained as a yellow solid (322 mg, 1.19 mmol, 95%). 1H NMR
(400 MHz, [D6]DMSO): d=7.63 (brs, 1H), 7.41 (d, 2H, J=8.2 Hz),
7.14 (d, 2H, J=8.2 Hz), 3.70 (m, 4H), 3.60 (m, 4H), 2.29 ppm (s,
3H); 13C NMR (101 MHz, [D6]DMSO): d=162.5 (C), 151.4 (C), 135.0
(C), 129.2 (2ꢃCH), 120.4 (2ꢃCH), 117.1 (C), 92.4 (C), 66.0 (2ꢃCH2),
48.7 (2ꢃCH2), 20.7 ppm (CH3); FTIR (neat): n˜ =3407, 3300, 3212,
2859, 2183, 1648, 1622, 1541, 1488, 1376, 1316, 1206, 1099, 993,
821 cmÀ1; LC-MS: m/z 272.20 [M+H]+; HRMS (ESI): m/z calcd for
C14H17N5O: 272.1511; found: 272.152.
2-(4-Methoxyphenylhydrazono)-2-cyano-N,N-pentamethylen-
acetamidine (2g): Product 2g was obtained from 1b and piperi-
dine 3b according to general procedure B. Compound 1b was dis-
solved in an EtOH/THF mixture (67:33, v/v). Product 2g was ob-
tained as
a
black solid (322 mg, 1.13 mmol, 90%). 1H NMR
2-(4-Methylphenylhydrazono)-2-cyano-N,N-(3-nitrosopentame-
thylen)-acetamidine (2l): Product 2l was obtained from 1c and pi-
perazine 3d according to general procedure B. Compound 1c was
dissolved in an EtOH/THF mixture (56:44, v/v). Product 2l was ob-
tained as a brown solid (331 mg, 1.23 mmol, 98%; mixture of iso-
(400 MHz, [D6]DMSO): d=7.47 (d, 2H, J=8.9 Hz), 7.43 (brs, 1H),
6.90 (d, 2H, J=8.9 Hz), 3.75 (s, 3H), 3.54 (m, 4H), 1.59 ppm (m,
6H); 13C NMR (101 MHz, [D6]DMSO): d=162.6 (C), 157.9 (C), 148.0
(C), 121.9 (2ꢃCH), 117.7 (C), 114.3 (2ꢃCH), 92.4 (C), 55.6 (CH3), 49.7
(2ꢃCH2), 26.1 (2ꢃCH2), 24.1 ppm (CH2); FTIR (neat): n˜ =2925, 2185,
1601, 1541, 1508, 1236, 1025, 832 cmÀ1; LC-MS: m/z 286.20 [M+
H]+; HRMS (ESI): m/z calcd for C15H19N5O: 286.1668; found:
286.1673.
1
mers 1 and 2). H NMR (400 MHz, [D6]DMSO): isomer 1: d=7.53 (s,
1H), 7.40 (d, 2H, J=8.2 Hz), 7.13 (d, 2H, J=8.1 Hz), 3.80 (m, 4H),
2.69 (m, 4H), 2.29 ppm (s, 3H); isomer 2: d=7.53 (s, 1H), 7.40 (d,
2H, J=8.2 Hz), 7.13 (d, 2H, J=8.1 Hz), 3.49 (m, 4H), 2.78 (m, 4H),
2.29 ppm (s, 3H); 13C NMR (101 MHz, [D6]DMSO): d=162.4 (C),
151.5 (C), 134.7 (C), 129.2 (2ꢃCH), 120.3 (2ꢃCH), 117.2 (C), 92.3 (C),
49.8 (2ꢃCH2), 45.6 (2ꢃCH2), 20.7 ppm (CH3); FTIR (neat): n˜ =3298,
2-(4-Methoxyphenylhydrazono)-2-cyano-N,N-(3-oxopentamethy-
len)-acetamidine (2h): Product 2h was obtained from 1b and
morpholine 3c according to general procedure B. Compound 1b
was dissolved in an EtOH/THF mixture (67:33, v/v). Product 2h was
obtained as a black solid (308 mg, 1.07 mmol, 86%). 1H NMR
(400 MHz, [D6]DMSO): d=7.56 (s, 1H), 7.48 (d, 2H, J=8.8 Hz), 6.91
(d, 2H, J=8.8 Hz), 3.76 (s, 3H), 3.69 (m, 4H), 3.59 ppm (m, 4H);
13C NMR (101 MHz, [D6]DMSO): d=162.5 (C), 157.7 (C), 147.5 (C),
121.7 (2ꢃCH), 117.2 (C), 113.9 (2ꢃCH), 92.1 (C), 66.0 (2ꢃCH2), 55.2
(CH3), 48.7 ppm (2ꢃCH2); FTIR (neat): n˜ =3282, 3199, 2912, 2858,
2174, 1599, 1544, 1388, 1314, 1238, 1103, 1020, 996, 830 cmÀ1; LC-
MS: m/z 288.17 [M+H]+; HRMS (ESI): m/z calcd for C14H17N5O2:
288.146; found: 288.1451.
3198, 2188, 1619, 1550, 1487, 1376, 1305, 1120, 1001, 823 cmÀ1
;
LC-MS: m/z 271.21 [M+H]+; HRMS (ESI): m/z calcd for C14H18N6:
271.1671; found: 271.1668.
2-(4-Fluorophenylhydrazono)-2-cyano-N,N-butylmethylen-acet-
amidine (2m): Product 2m was obtained from 1c and pyrrolidine
3a according to general procedure B. Compound 1d was dissolved
in an EtOH/THF mixture (67:33, v/v). Product 2m was obtained as
a dark-green solid (288 mg, 1.11 mmol, 89%). 1H NMR (400 MHz,
[D6]DMSO): d=7.52 (m, 2H), 7.25–7.30 (brs, 1H), 7.14 (t, 2H, J=
8.6 Hz), 3.57–3.68 (m, 4H), 1.89–1.98 ppm (m, 4H); 13C NMR
(101 MHz, [D6]DMSO): d=160.0 (d, C, J=242 Hz), 158.3 (C), 150.4
(C), 121.8 (d, 2 CH, J=8 Hz), 117.1 (C), 115.3 (d, 2 CH, J=22 Hz),
92.2 (C), 49.7 (2ꢃCH2), 24.8 ppm (2ꢃCH2); FTIR (neat): n˜ =3387,
2-(4-Methoxyphenylhydrazono)-2-cyano-N,N-(3-nitrosopentame-
thylen)-acetamidine (2i): Product 2i was obtained from 1b and
piperazine 3d according to general procedure B. Compound 1b
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3301, 3206, 2972, 2187, 1596, 1551, 1477, 1375, 1355, 1210,
837 cmÀ1; LC-MS: m/z 260.18 [M+H]+; HRMS (ESI): m/z calcd for
C13H14FN5: 260.1311; found: 260.1316.
material was suspended in dichloromethane (2.0 mL) and passed
through a two-layer pad of celite and silica gel. The pad was
washed with dichloromethane (2ꢃ5.0 mL). Evaporation of the fil-
trate was performed to obtain triazole compounds 4a–o.
2-(4-Fluorophenylhydrazono)-2-cyano-N,N-pentamethylen-acet-
amidine (2n): Product 2n was obtained from 1d and piperidine
3b according to general procedure B. Compound 1d was dis-
solved in an EtOH/THF mixture (67:33, v/v). Product 2n was ob-
tained as a dark-green solid (297 mg, 1.08 mmol, 87%). 1H NMR
(400 MHz, [D6]DMSO): d=7.59 (brs, 1H), 7.52 (dd, 2H, J=8.9,
5.4 Hz), 7.14 (t, 2H, J=8.8 Hz), 3.57 (m, 4H), 1.64 ppm (s, 6H);
13C NMR (101 MHz, [D6]DMSO): d=162.2 (C), 161.5 (d, C, J=
214.9 Hz), 150.4 (C), 121.8 (d, 2 CH, J=8.1 Hz), 117.0 (C), 115.3 (d, 2
CH, J=22.7 Hz), 92.6 (C), 49.3 (2ꢃCH2), 25.6 (2ꢃCH2), 23.6 ppm
(CH2); FTIR (neat): n˜ =3395, 3298, 3203, 2933, 2184, 1619, 1560,
1478, 1379, 1360, 1313, 1195, 1089, 994, 842 cmÀ1; LC-MS: m/
z 274.23 [M+H]+; HRMS (ESI): m/z calcd for C14H16FN5: 274.1468;
found: 274.1465.
2-Phenyl-4-cyano-5-amino-2H-[1,2,3]-triazole (4a): Product 4a
was obtained from 2a according to general procedure C as an off-
white solid (18.5 mg, 1.00 mmol, 50%). 1H NMR (400 MHz,
[D6]DMSO): d=7.90 (d, 2H, J=8.0 Hz), 7.56 (t, 2H, J=7.6 Hz), 7.44
(t, 1H, J=7.4 Hz), 6.61 ppm (s, 2H); 13C NMR (101 MHz, [D6]DMSO):
d=156.8 (C), 138.6 (C), 129.6 (2ꢃCH), 128.2 (CH), 118.5 (2ꢃCH),
112.2 (C), 107.8 ppm (C); FTIR (neat): n˜ =3395, 3329, 2922, 2852,
2235, 1637, 1560, 1488, 1333, 1322, 963, 763, 647 cmÀ1; LC-MS: m/
z 186.1 [M+H]+.
2-Phenyl-4-cyano-5-pyrrolidin-1-yl-2H-[1,2,3]-triazole (4b): Prod-
uct 4b was obtained from 2b according to general procedure C as
an orange solid (42 mg, 0.176 mmol, 87%). 1H NMR (400 MHz,
[D6]DMSO): d=7.94 (d, 2H, J=7.8 Hz), 7.57 (t, 2H, J=7.8 Hz), 7.45
(t, 1H, J=7.3 Hz), 3.51 (t, 4H, J=6.4 Hz), 1.97 ppm (t, 4H, J=
6.4 Hz); 13C NMR (101 MHz, [D6]DMSO): d=155.7 (C), 138.3 (C),
129.8 (2ꢃCH), 128.4 (CH), 118.4 (2ꢃCH), 113.8 (C), 105.8 (C), 48.2
(2ꢃCH2), 25.0 ppm (2ꢃCH2); FTIR (neat): n˜ =2923, 2873, 2224,
1583, 1496, 1458, 961, 759, 689 cmÀ1; LC-MS: m/z 240.3 [M+H]+;
HRMS (ESI): m/z calcd for C13H13N5: 240.1249; found: 240.1244.
2-(4-Nitrophenylhydrazono)-2-cyano-N,N-(3-oxopentamethylen)-
acetamidine (2o): Product 2o was obtained from 1e and morpho-
line 3c according to general procedure B. Compound 1e was dis-
solved in THF. Product 2o was obtained as a red solid (328 mg,
1.08 mmol, 87%). 1H NMR (400 MHz, [D6]DMSO): d=8.16 (d, 2H,
J=9.0 Hz), 8.09 (brs, 1H), 7.61 (d, 2H, J=9.0 Hz), 3.73 (d, 4H, J=
4.6 Hz), 3.67 ppm (d, 4H, J=4.5 Hz); 13C NMR (101 MHz, [D6]DMSO):
d=161.8 (C), 158.8 (C), 143.2 (C), 124.8 (2ꢃCH), 120.3 (2ꢃCH),
115.7 (C), 96.4 (C), 65.9 (2ꢃCH2), 48.9 ppm (2ꢃCH2); FTIR (neat): n˜ =
3415, 3373, 3277, 3181, 2198, 1558, 1490, 1307, 1093, 1018, 1000,
845 cmÀ1; LC-MS: m/z 303.15 [M+H]+; HRMS (ESI): m/z calcd for
C13H14N6O3: 303.1205; found: 303.1207.
2-Phenyl-4-cyano-5-piperidin-1-yl-2H-[1,2,3]-triazole (4c): Prod-
uct 4c was obtained from 2c according to general procedure C as
an off-white solid (48 mg, 0.190 mmol, 95%). 1H NMR (400 MHz,
[D6]DMSO): d=7.95 (d, 2H, J=7.8 Hz), 7.58 (t, 2H, J=7.8 Hz), 7.47
(t, 4H, J=7.4 Hz), 3.46–3.52 (m, 4H), 1.55–1.70 ppm (m, 6H);
13C NMR (101 MHz, [D6]DMSO): d=157.9 (C), 138.2 (C), 129.8 (2ꢃ
CH), 128.6 (CH), 118.5 (2ꢃCH), 113.6 (C), 107.0 (C), 48.0 (2ꢃCH2),
24.3 (2ꢃCH2), 23.3 ppm (CH2); FTIR (neat): n˜ =2924, 2852, 2228,
1542, 1241, 966, 760, 722, 688, 649 cmÀ1; LC-MS: m/z 254.3 [M+
H]+; HRMS (ESI): m/z calcd for C14H15N5: 254.1405; found: 254.1384.
2-(4-Carbethoxyhydrazono)-2-cyano-N,N-(3-oxopentamethylen)-
acetamidine (2p): Product 2p was obtained from 1 f and morpho-
line 3c according to general procedure B. Compound 1 f was dis-
solved in an EtOH/THF mixture (75:25, v/v). Product 2p was ob-
tained as a dark-red solid (391 mg, 1.18 mmol, 95%). 1H NMR
(400 MHz, [D6]DMSO): d=7.96 (brs, 1H), 7.91 (d, 2H, J=8.5 Hz),
7.56 (d, 2H, J=8.5 Hz), 4.29 (q, 2H, J=7.1 Hz), 3.72 (m, 4H), 3.63
(m, 4H), 1.33 ppm (t, 3H, J=7.1 Hz); 13C NMR (101 MHz,
[D6]DMSO): d=165.6 (C), 162.2 (C), 157.0 (C), 130.0 (2ꢃCH), 125.7
(C), 120.2 (2ꢃCH), 116.2 (C), 94.5 (C), 65.9 (2ꢃCH2), 60.4 (CH2), 48.8
(2ꢃCH2), 14.2 ppm (CH3); FTIR (neat): n˜ =3310, 3198, 2974, 2185,
1698, 1542, 1355, 1266, 1212, 1095, 998, 857, 772 cmÀ1; LC-MS: m/
z 330.18 [M+H]+; HRMS (ESI): m/z calcd for C16H19N5O3: 330.1566;
found: 330.1581.
2-Phenyl-4-cyano-5-morpholino-1-yl-2H-[1,2,3]-triazole
(4d):
Product 4d was obtained from 2d according to general procedure
1
C as a yellow solid (35 mg, 0.137 mmol, 68%). H NMR (400 MHz,
[D6]DMSO): d=7.95 (d, 2H, J=7.8 Hz), 7.58 (t, 2H, J=7.5 Hz), 7.48
(t, 1H, J=7.5 Hz), 3.77 (m, 4H), 3.46 ppm (m, 4H); 13C NMR
(101 MHz, [D6]DMSO): d=157.9 (C), 138.2 (C), 129.8 (2ꢃCH), 128.8
(CH), 118.6 (2ꢃCH), 113.3 (C), 107.3 (C), 65.2 (2ꢃCH2), 47.1 ppm (2ꢃ
CH2); FTIR (neat): n˜ =2924, 2855, 2233, 1542, 1498, 1454, 1373,
1265, 1229, 1116, 927, 753, 680 cmÀ1; LC-MS: m/z 256.17 [M+H]+;
HRMS (ESI): m/z calcd for C13H13N5O: 256.1198; found: 256.1192.
2-Phenyl-4-cyano-5-piperazin-1-yl-2H-[1,2,3]-triazole (4e): Prod-
uct 4e was obtained from 2e according to general procedure C as
an off-white solid (24 mg, 0.094 mmol, 48%). 1H NMR (400 MHz,
[D6]DMSO): d=9.09 (brs, 1H), 7.97 (d, 2H, J=8.0 Hz), 7.60 (t, 2H,
J=7.6 Hz), 7.50 (m, 1H), 3.68 (m, 4H), 3.48 (brs, 1H), 3.32 ppm (m,
4H); 13C NMR (101 MHz, [D6]DMSO): d=157.0 (C), 138.2 (C), 129.9
(2ꢃCH), 128.9 (CH), 118.6 (2ꢃCH), 112.9 (C), 107.9 (C), 44.2 (2ꢃ
CH2), 41.8 ppm (2ꢃCH2); FTIR (neat): n˜ =2704, 2492, 2232, 1672,
1535, 1184, 1119, 968, 831, 722 cmÀ1; LC-MS: m/z 255.37 [M+H]+.
General procedure C for the synthesis of 5-amino-2-aryl-2H-
[1,2,3]-triazole-4-carbonitriles 4a–p
Sample loop A (1.0 mL) was filled with a solution of acetamidine
derivatives 2a–p (0.20 mmol, 0.20m) in DMF and sample loop B
(1.0 mL) was filled with a solution containing copper acetate
(0.02 mmol, 0.02m) and sodium periodate (0.24 mmol, 0.24m) in
DMF. The two sample loops were simultaneously switched into line
and the starting materials were pumped through the system with
DMF as a solvent at a flow rate of 0.20 mLminÀ1 (for each line).
The starting solutions were mixed by using an arrowhead T-mixing
piece (I.D.=1.4 mm) and pumped (combined flow rate=
0.40 mLminÀ1) through a PFA coil reactor (14.0 mL, I.D.=1.0 mm;
residence time=35 min) heated at 1208C. The reaction mixture
passed through a back-pressure regulator (4 bar) before exiting the
system. The back-pressure regulator was located in a sonicator
bath due to precipitation inside the reactor. Sonication was period-
ically switch on (20 s every 1 min) to avoid clogging of the system.
The collected fractions were evaporated to dryness, and the crude
2-(4-Methoxyphenyl)-4-cyano-5-pyrrolidin-1-yl-2H-[1,2,3]-triazole
(4 f): Product 4 f was obtained from 2 f according to general proce-
dure C as an off-white solid (44 mg, 0.163 mmol, 82%). 1H NMR
(400 MHz, [D6]DMSO): d=7.85 (d, 2H, J=8.9 Hz), 7.10 (d, 2H, J=
8.9 Hz), 3.81 (s, 3H), 3.45–3.53 (m, 4H), 1.93–2.01 ppm (m, 4H);
13C NMR (101 MHz, [D6]DMSO): d=159.2 (C), 155.7 (C), 132.0 (C),
120.1 (2ꢃCH), 114.8 (2ꢃCH), 113.9 (C), 104.8 (C), 55.6 (CH3), 48.2
(2ꢃCH2), 25.0 ppm (2ꢃCH2); FTIR (neat): n˜ =2924, 2225, 1591,
1516, 1028, 966, 825, 798 cmÀ1; LC-MS: m/z 270.23 [M+H]+; HRMS
(ESI): m/z calcd for C14H15N5O: 270.1355; found: 270.1342.
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2-(4-Methoxyphenyl)-4-cyano-5-piperidin-1-yl-2H-[1,2,3]-triazole
(4g): Product 4g was obtained from 2g according to general pro-
cedure C as an off-white solid (55 mg, 0.194 mmol, 98%). H NMR
2989, 2496, 2236, 1669, 1540, 1508, 1175, 1116, 966, 835, 817, 795,
722 cmÀ1; LC-MS: m/z 269.18 [M+H]+; HRMS (ESI): m/z calcd for
C14H16N6: 269.1515; found: 269.1501.
1
(400 MHz, [D6]DMSO): d=7.87 (d, 2H, J=9.1 Hz), 7.11 (d, 2H, J=
9.1 Hz), 3.82 (s, 3H), 3.43–3.50 (m, 4H), 1.58–1.69 ppm (m, 6H);
13C NMR (101 MHz, [D6]DMSO): d=159.7 (C), 158.3 (C), 132.3 (C),
120.6 (2ꢃCH), 115.2 (2ꢃCH), 114.2 (C), 106.5 (C), 56.0 (CH3), 48.4
(2ꢃCH2), 24.8 (2ꢃCH2), 23.7 ppm (CH2); FTIR (neat): n˜ =2923, 2852,
2225, 1542, 1512, 1238, 1029, 968, 826 cmÀ1; LC-MS: m/z 284.2
[M+H]+; HRMS (ESI): m/z calcd for C15H17N5O: 284.1511; found:
284.1499.
2-(4-Fluorophenyl)-4-cyano-5-pyrrolidin-1-yl-2H-[1,2,3]-triazole
(4m): Product 4m was obtained from 2m according to general
procedure C as a brown solid (50 mg, 0.195 mmol, 97%). H NMR
1
(400 MHz, [D6]DMSO): d=7.95 (m, 2H), 7.41 (t, 2H, J=8.7 Hz), 3.50
(t, 4H, J=6.4 Hz), 1.97 ppm (t, 4H, J=6.4 Hz); 13C NMR (101 MHz,
[D6]DMSO): d=161.8 (d, C, J=245.5 Hz), 156.1 (C), 135.3 (C), 121.1
(d, 2 CH, J=9.2 Hz), 117.1 (d, 2 CH, J=23.7 Hz), 114.1 (C), 106.2 (C),
48.6 (2ꢃCH2), 25.4 ppm (2ꢃCH2); FTIR (neat): n˜ =2923, 2227, 1589,
1507, 1458, 1216, 1096, 961, 837, 669 cmÀ1; LC-MS: m/z 258.21
[M+H]+; HRMS (ESI): m/z calcd for C13H12FN5: 258.1155; found:
258.1154.
2-(4-Methoxyphenyl)-4-cyano-5-morpholino-1-yl-2H-[1,2,3]-tria-
zole (4h): Product 4h was obtained from 2h according to general
1
procedure C as a brown solid (52 mg, 0.182 mmol, 92%). H NMR
(400 MHz, [D6]DMSO): d=7.87 (d, 2H, J=8.7 Hz), 7.11 (d, 2H, J=
8.7 Hz), 3.83 (s, 3H), 3.77 (m, 4H), 3.44 ppm (m, 4H); 13C NMR
(101 MHz, [D6]DMSO): d=159.4 (C), 157.9 (C), 131.9 (C), 120.3 (2ꢃ
CH), 114.8 (2ꢃCH), 113.5 (C), 106.4 (C), 65.2 (2ꢃCH2), 55.6 (CH3),
47.2 ppm (2ꢃCH2); FTIR (neat): n˜ =2921, 2852, 2229, 1541, 1515,
1458, 1255, 1120, 1031, 827, 654 cmÀ1; FTIR (neat): n˜ =2920, 2851,
2-(4-Fluorophenyl)-4-cyano-5-piperidin-1-yl-2H-[1,2,3]-triazole
(4n): Product 4n was obtained from 2n according to general pro-
cedure C as an off-white solid (42 mg, 0.155 mmol, 77%). H NMR
1
(400 MHz, [D6]DMSO): d=8.00 (m, 2H), 7.43 (t, 2H, J=8.8 Hz), 3.48
(m, 4H), 1.56–1.69 ppm (m, 6H); 13C NMR (101 MHz, [D6]DMSO):
d=165.1 (d, C, J=377.1 Hz), 158.4 (C), 135.2 (C), 121.3 (d, 2 CH, J=
9.2 Hz), 117.1 (d, 2 CH, J=22.9 Hz), 114.0 (C), 107.5 (C), 48.4 (2ꢃ
CH2), 24.7 (2ꢃCH2), 23.7 ppm (CH2); FTIR (neat): n˜ =2952, 2931,
2856, 2229, 1545, 1508, 1221, 967, 835 cmÀ1; LC-MS: m/z 272.20
[M+H]+; HRMS (ESI): m/z calcd for C14H14FN5: 272.1311; found:
272.1321.
2229, 1541, 1512, 1458, 1255, 1121, 1032, 967, 925, 828, 653 cmÀ1
;
LC-MS: m/z 286.2 [M+H]+; HRMS (ESI): m/z calcd for C14H15N5O2:
286.1304; found: 286.1292.
2-(4-Methoxyphenyl)-4-cyano-5-piperazin-1-yl-2H-[1,2,3]-triazole
(4i): Product 4i was obtained from 2i according to general proce-
dure C as an off-white solid (12 mg, 0.042 mmol, 22%); 1H NMR
(400 MHz, [D6]DMSO): d=9.12 (brs, 1H), 7.89 (d, 2H, J=9.0 Hz),
7.13 (d, 2H, J=9.0 Hz), 3.83 (s, 3H), 3.69 (t, 4H, J=4.6 Hz),
3.32 ppm (m, 4H); 13C NMR (101 MHz, [D6]DMSO): d=159.5 (C),
157.0 (C), 131.8 (C), 120.3 (2ꢃCH), 114.9 (2ꢃCH), 113.1 (C), 107.0
(C), 55.6 (CH3), 44.3 (2ꢃCH2), 41.8 ppm (2ꢃCH2); FTIR (neat): n˜ =
2973, 2731, 2237, 1669, 1540, 1509, 1250, 1169, 1125, 1020, 967,
835, 827, 721 cmÀ1; LC-MS: m/z 285.21 [M+H]+; HRMS (ESI): m/z
calcd for C14H16N6O: 285.1464; found: 285.1483.
2-(4-Nitrophenyl)-4-cyano-5-morpholino-1-yl-2H-[1,2,3]-triazole
(4o): Product 4o was obtained from 2o according to general pro-
cedure C as a brown solid (50 mg, 0.167 mmol, 83%). 1H NMR
(400 MHz, [D6]DMSO): d=8.43 (d, 2H, J=9.2 Hz), 8.18 (d, 2H, J=
9.2 Hz), 3.79 (m, 4H), 3.50 ppm (m, 4H); 13C NMR (101 MHz,
[D6]DMSO): d=158.4 (C), 146.9 (C), 142.3 (C), 126.0 (2ꢃCH), 119.7
(2ꢃCH), 113.3 (C), 109.9 (C), 65.6 (2ꢃCH2), 47.4 ppm (2ꢃCH2); FTIR
(neat): n˜ =2922, 2235, 1569, 1541, 1524, 1350, 1337, 1320, 1261,
1222, 1109, 965, 835, 748 cmÀ1; LC-MS: m/z 301.2 [M+H]+; HRMS
(ESI): m/z calcd for C13H12N6O3: 301.1049; found: 301.1064.
2-(4-Methylphenyl)-4-cyano-5-piperidin-1-yl-2H-[1,2,3]-triazole
(4j): Product 4j was obtained from 2j according to general proce-
dure C as an off-white solid (43 mg, 0.161 mmol, 80%). 1H NMR
(400 MHz, [D6]DMSO): d=7.82 (d, 2H, J=8.4 Hz), 7.36 (d, 2H, J=
8.4 Hz), 3.43–3.50 (m, 4H), 2.36 (s, 3H), 1.54–1.69 ppm (m, 6H);
13C NMR (101 MHz, [D6]DMSO): d=157.9 (C), 138.4 (C), 136.2 (C),
130.1 (2ꢃCH), 118.5 (2ꢃCH), 113.7 (C), 106.6 (C), 48.0 (2ꢃCH2), 24.3
(2ꢃCH2), 23.3 (CH2), 20.6 ppm (CH3); FTIR (neat): n˜ =2936, 2857,
2225, 1542, 1513, 1452, 1239, 969, 818 cmÀ1; LC-MS: m/z 268.3
[M+H]+; HRMS (ESI): m/z calcd for C15H17N5: 268.1562; found:
268.1549.
2-(4-Carbethoxyphenyl)-4-cyano-5-morpholino-1-yl-2H-[1,2,3]-tri-
azole (4p): Product 4p was obtained from 2p according to gener-
al procedure C as a brown solid (40 mg, 0.122 mmol, 61%).
1H NMR (400 MHz, [D6]DMSO): d=8.14 (d, 2H, J=8.8 Hz), 8.08 (d,
2H, J=8.8 Hz), 4.35 (q, 2H, J=7.1 Hz), 3.78 (m, 4H), 3.48 (m, 4H),
1.34 ppm (t, 3H, J=7.1 Hz); 13C NMR (101 MHz, [D6]DMSO): d=
164.8 (C), 158.0 (C), 141.0 (C), 130.9 (2ꢃCH), 129.5 (C), 118.6 (2ꢃ
CH), 113.0 (C), 108.5 (C), 65.2 (2ꢃCH2), 61.1 (CH2), 47.0 (2ꢃCH2),
14.1 ppm (CH3); FTIR (neat): n˜ =2923, 2236, 1715, 1542, 1265, 1051,
963, 852, 766 cmÀ1; LC-MS: m/z 328.20 [M+H]+; HRMS (ESI): m/z
calcd for C16H17N5O3, 328.141; found: 328.1395.
2-(4-Methylphenyl)-4-cyano-5-morpholino-1-yl-2H-[1,2,3]-triazole
(4k): Product 4k was obtained from 2k according to general pro-
1
cedure C as an off-white solid (50 mg, 0.186 mmol, 93%). H NMR
(400 MHz, [D6]DMSO): d=7.84 (d, 2H, J=8.4 Hz), 7.38 (d, 2H, J=
8.4 Hz), 3.77 (m, 4H), 3.45 (m, 4H), 2.37 ppm (s, 3H); 13C NMR
(101 MHz, [D6]DMSO): d=158.3 (C), 138.9 (C), 136.5 (C), 130.6 (2ꢃ
CH), 118.9 (2ꢃCH), 113.8 (C), 107.2 (C), 65.6 (2ꢃCH2), 47.5 (2ꢃCH2),
21.0 ppm (CH3); FTIR (neat): n˜ =2922, 2857, 2232, 1541, 1120, 969,
938, 924, 811 cmÀ1; LC-MS: m/z 270.20 [M+H]+; HRMS (ESI): m/z
calcd for C14H15N5O: 270.1355; found: 270.1342.
Acknowledgements
We gratefully acknowledge funding from the Walloon Region
(Belgium)–DGO6 (Convention 6534).
Keywords: diazonium ions · flow chemistry · heterocycles ·
library synthesis · triazoles
2-(4-Methylphenyl)-4-cyano-5-piperazin-1-yl-2H-[1,2,3]-triazole
(4l): Product 4l was obtained from 2l according to general proce-
dure C as a brown solid (35 mg, 0.131 mmol, 65%). 1H NMR
(400 MHz, [D6]DMSO): d=8.95 (brs, 1H), 7.86 (d, 2H, J=8.5 Hz),
7.40 (d, 2H, J=8.5 Hz), 3.69 (t, 4H, J=4.8 Hz), 3.30 (m, 4H),
2.38 ppm (s, 3H); 13C NMR (101 MHz, [D6]DMSO): d=157.0 (C),
138.8 (C), 136.0 (C), 130.2 (2ꢃCH), 118.6 (2ꢃCH), 113.0 (C), 107.5
(C), 44.2 (2ꢃCH2), 41.8 (2ꢃCH2), 20.6 ppm (CH3); FTIR (neat): n˜ =
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Received: February 7, 2014
Revised: May 28, 2014
Published online on July 30, 2014
Chem. Eur. J. 2014, 20, 12223 – 12233
www.chemeurj.org
12233
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim